The present invention relates to prostacyclin derivative containing compositions, more specifically to prostacyclin derivative containing compositions suitable for use in the treatment of cancer.
Prostaglandins are hormone-like substances found in the tissues and organs of the body. No other autocoids or hormones show more numerous or diverse biologically active effects than prostaglandins. They have been found to affect several body systems, including the central nervous, cardiovascular, gastrointestinal, urinary, and endocrine systems. Their effects on the endocrine system include stimulating the release of growth hormone by the pituitary gland, mediating the effects of luteinizing hormone on the ovary, stimulating the dissolution of the corpus luteum, and altering steroid hormone synthesis by the adrenal cortex. One prostaglandin compound has been found to be a powerful stimulant of uterine contractions and may prove useful for inducing labor.
Prostacyclin (a prostaglandin analog) is believed to act on the target cells via cellular surface receptors. These receptors are believed to be part of second messenger systems by which prostaglandin action is mediated. These compounds are known to be responsible in part to regulating a range of physiological responses including, for example, inflammation, blood pressure, blood clotting, fever, pain, induction of labor, and the sleep/wake cycle, and therefore are useful for preventing, controlling and treating a variety of diseases and pathological conditions in warm-blooded animals including humans.
Cancer is a disorder of cell growth that is typically characterized by invasion and destruction of surrounding healthy tissue by abnormal cells. Cancer cells typically arise from normal cells whose nature is permanently changed. They often multiply more rapidly than healthy body cells and do not seem subject to normal control by nerves and hormones. They may spread via the bloodstream or lymphatic system to other parts of the body, where they form metastatic clusters or nodules to produce further tissue damage (metastases). The ability of cancer cells to proliferate and metastasize is a major obstacle in the search for a treatment or cure. The mortality rate of cancer patients is closely linked to recurrence of metastatic cancer cells or malignant tumors. Certain classes of anticancer compounds are capable of inhibiting the spread of malignant tumors by inhibiting one or more steps of the process of tumor growth, migration and dissemination. Such compounds can improve the mortality rate among cancer patients.
The development of a metastasis represents the terminal stage of a complex series of events in which malignant cancer cells, spread to distant sites principally by way of the circulatory system. The first step of metastatic cascade usually involves cancer cell detachment from the primary tumor into newly formed tumor blood vessels. After cancer cell entry into the circulation, cancer cells interact with cellular and non-cellular components of the blood. Thereafter, circulating cancer cells attach to endothelial lining and penetrate into surrounding tissue. Although most cancer cells dispersed through this route die, a small number of cancer cells are able to complete all the steps of the metastatic cascade. Such cancer cells possess inherent biological properties that facilitate their survival, and are usually characterized by high invasiveness and motility. It is noted that the biochemistry underlying the process of the metastatic cascade is not entirely understood, however, it is believed that surface adhesion proteins, organelles or cell surface structures (e.g. invadopodia) and protease each may play a role in the cascade process. See, for example, Mueller S. C., Ghersi G., Akiyama S. K., Sang Q. X., Howard L., Pineiro-Sanchez M., Nakahara H., Yeh Y., Chen W. T. (1999) J. Biol. Chem. August 27, 274(35): 24947-52; and Chen W. T., Lee C. C., Goldstein L., Bernier S., Liu C. H., Lin C. Y., Yeh Y., Monsky W. L., Kelly T., Dai M. et al (1994) Breast Cancer Res. Treat. 31(2-3): 217-226.
One of these survival-enhancing properties may be the ability to interact with and attach to host platelets in the bloodstream, thus improving their potential to lodge in the microvasculature and adhere to the vascular endothelium lining. Alternatively, once lodged, cancer cells may initiate the formation of surrounding, protective platelet thrombi and enzymatic degradation of protein in the extracellular matrix, until extravasation or infiltration of the cancer cells through the blood vessel walls into surrounding tissue, is completed.
Anticoagulant therapy with aspirin, dipyridamole, heparin, and warfarin has been attempted in the hope of preventing metastasis. However, results to date have been inconclusive. On the other hand, prostaglandin compounds and analogs thereof including prostacyclin and derivatives thereof that are generally known potent anti-thrombogenic agents have been investigated with promising results for possessing potent inhibitory effects on tumor metastasis.
Studies have shown that prostaglandin compounds and analogs thereof function primarily by interfering with cancer cell-host interactions (such as cancer cell induced platelet aggregation, cancer cell adhesion to endothelial cells and sub-endothelial matrix, cancer cell induced endothelial cell retraction, protein degradation of the extracellular matrix, etc.) to produce such antimetastatic effects. Such compounds have also been found to exert protective effects in maintaining vascular and platelet homeostasis and preserving the integrity of the extracellular matrix to deter tumor growth, extravasation, and metastasis.
For example, U.S. Pat. No. 5,545,671 discloses prostacyclin derivatives Eptaloprost and Cicaprost as antimetastatic agents in combination with a physiologically compatible base and a cyclodextrin clathrate. U.S. Pat. No. 4,950,680 discloses the combination of a prostacyclin and a calcium channel blocker to prevent tumor induced platelet aggregation. U.S. Pat. No. 5,877,215 is directed to a method of increasing the cytotoxic effect of ionization radiation by the administration of a prostaglandin compound, especially prostaglandin D2 or xcex9412-prostaglandin J2. U.S. Pat. No. 5,914,322 is directed to a topically applied treatment for skin cancers including a drug that inhibits prostaglandin synthesis, preferably a non-steroidal anti-inflammatory drug such as diclofenac. U.S. Pat. No. 5,496,850 discloses the use of a prostaglandin derivative, beraprost for the treatment of cancer.
Further studies performed to date also indicate that prostacyclin derivatives have a spectrum of activity against a wide variety of cancer types. Particularly, many of such prostacyclin derivatives have been shown to possess potent inhibitory effects on cancer cell metastasis in several different animal models including both experimental and spontaneous metastasis models. See, for example, Honn K V et al.: xe2x80x9cProstacyclin: a Potent Antimetastatic Agentxe2x80x9d, Science 212: 1270-72 (1981); Carteni et al.: xe2x80x9cBiological activity of prostacyclin in patients with malignant bone and soft tissue tumorsxe2x80x9d, J. Cancer Res. Clin. Oncol. 116 Suppl. Part 1: 631 (1990); Schneider et al.: xe2x80x9cAntimetastatic Prostacyclin Analogsxe2x80x9d, Drugs Future 18:29-48 (1993); Daneker et al.: xe2x80x9cAntimetastatic prostacyclins inhibit E-selectin mediated adhesion of colon carcinoma to endothelial cellsxe2x80x9d, Journal of Cellular Biochemistry Supplement 19B:25 (1995); and Schirner et al.: xe2x80x9cInhibition of metastasis by Cicaprost in rats with established SMT2A mammary carcinoma growthxe2x80x9d, Cancer Detection and Prevention, 21(1): 44-50 (1997). In addition, prostacyclin derivatives have been shown to possess antiproliferative effects in cells and apoptosis effects in cancer cells.
It would therefore be a significant advance in the art of drug therapy, especially in the treatment of cancer, if pharmaceutical compositions employing prostacyclin derivatives could be employed for the inhibition of protein degradation including those caused by cancer cells, within the extracellular matrix of tissue and the like, and the treatment of cancer including, but not limited to, inhibiting metastasis of cancer cells, controlling cell proliferation in cancer cells, and promoting apoptosis in cancer cells.
The present invention is generally directed to pharmaceutical compositions comprising prostacyclin derivatives that possess pharmaceutical activity useful for the treatment of cancer and methods of using the same for the treatment of cancer in warm-blooded animals including humans. The present invention provides pharmaceutical compositions useful for the inhibition of protein degradation including those caused by cancer cells, within the extracellular matrix of tissue and the like, and the treatment of cancer including, but not limited to, inhibiting metastasis of cancer cells, controlling cell proliferation in cancer cells, and promoting apoptosis in cancer cells.
The pharmaceutical compositions of the present invention comprise, in combination with a pharmaceutically acceptable carrier, at least one prostacyclin derivative selected from compounds of Formula I and pharmaceutically acceptable salts and esters thereof, 
wherein:
n is 0 or 1;
R1 is selected from the group consisting of O, N, S and C;
R2 is an alkyl group having at least one carbon atom, preferably 1 to 6 carbon atoms;
X is selected from O or NH; and
R is selected from hydrogen or an alkyl group having at least one carbon atom, preferably 1 to 6 carbon atoms.
A particularly preferred prostacyclin derivative is represented by Formula II, and includes salts and esters thereof. 
In one aspect of the present invention, the pharmaceutical composition comprises, in combination with a pharmaceutically acceptable carrier, a cancer-treating effective amount of at least one prostacyclin derivative selected from the compounds of Formula I and pharmaceutically acceptable salts and esters thereof.
In another aspect of the present invention, the pharmaceutical compositions may comprise a pharmaceutically acceptable carrier, and therapeutically effective amounts of at least one prostacyclin derivative selected from the compounds of Formula I and pharmaceutically acceptable salts and esters thereof, suitable for the inhibition of protein degradation including those caused by cancer cells, within the extracellular matrix of tissue and the like, and the treatment of cancer including, but not limited to, inhibiting metastasis of cancer cells, controlling cell proliferation in cancer cells, and promoting apoptosis in cancer cells.
In another particular aspect of the present invention, there is provided a method of treating warm-blooded animals including humans afflicted with cancer comprising administering to the warm-blooded animal a therapeutically effective amount of the pharmaceutical composition of the present invention.
In a further aspect of the present invention, there are provided methods of inhibiting metastasis of cancer cells, controlling cell proliferation in cancer cells, promoting apoptosis in cancer cells, inhibiting protein degradation such as caused by cancer cells in extracellular matrix of normal tissue, and the like, comprising administering to a warm-blooded animal including humans afflicted with cancer, a therapeutically effective amount of the pharmaceutical compositions of the present invention.
The present invention is further directed to a kit including pharmaceutical composition of the present invention and instructions for administration of the composition to warm-blooded animals, including humans.